The p53 protein is required for normal embryogenesis, tumor suppression, and cellular response to DNA damage. Activity of p53 not only guards cellular integrity but also prevents propagation of permanently damaged cells by inducing growth arrest or apoptosis. p53 is the most frequently inactivated protein in human cancer. A mutation of p53 is found in almost 50% of human cancers.
Under normal conditions, cellular regulator MDM2 controls p53 through an autoregulatory feedback loop. p53 activates MDM2 expression, leading to the expression of p53. MDM2 mediates ubiquitin-dependent degradation of p53 and is also a cofactor for E2F, which is involved in cell cycle regulation. The feedback control loop ensures that both MDM2 and p53 are kept at a low level in normal proliferating cells.
Overexpression of MDM2 has been found in many human malignancies. Accordingly, activation of the p53 pathway through inhibition of MDM2 has been proposed as a cancer therapy. Several studies have shown that p53 function can be reactivated by disrupting MDM2-p53 interaction, or by suppressing MDM2 expression. A variety of small molecules have been shown to bind p53, including Nutlin-3 and MI-219.
Overexpression of MDMX, which is structurally similar to MDM2, has also been found in many human malignancies. MDMX binds MDM2 and stimulates MDM2 degradation of p53. Only a few MDMX inhibitors have been identified to date. Many small molecules that inhibit MDM2, such as Nutlin, are virtually inactive in MDMX inhibition and fail to induce MDMX degradation in tumor cells. p53 activation by many small molecules is compromised in cells that overexpress MDMX. Small molecules that target both MDM2 and MDMX, and those that show preference for MDMX, would therefore be of great benefit in regulating p53 activity.